The present invention relates to a novel series of 4-phenylpiperazines, 4-phenylpiperidines and 4-phenyl-1,2,3,6-tetrahydropyridines. Having effects on both central serotonin 5-HT1A and dopamine D2 receptors, the novel compounds are useful in the treatment of certain psychic and neurologic disorders.
In International patent publication No. WO 92/03426, a class of piperazine derivatives having phenyl, naphtyl or quinolyl in the 4-position and an N-aryl substituted carbamoyl alkyl group or an N-aryl substituted ureido alkyl group in the 1-position is described. Said compounds are claimed to exhibit affinity for various receptors, including 5-HT2, 5-HT1A, alpha and dopamine receptors.
EP A1 0376607 relates to certain 1-[4-(3-indolyl)butyl]-4-(2-oxyphenyl)piperazine compounds being partial 5-HT1A agonists.
EP A1 0526434 among a number of other compounds, describes 1-[(4-phenylpiperazin-1-yl)-C2-6 alkyl]-benzimidazol-2-one compounds said to show 5-HT1A agonistic activity and 5-HT2A antagonistic activity.
U.S. Pat. No. 3,374,237 discloses a class of 1-phenyl-3-(4-phenyl-1-piperazinyl-C2-4 alkyl)-2-imidazolidinones claimed to be useful as tranquilizers. No test data at all are presented. FR Patents Nos 1.394.708 and 1.513.604, respectively, describe similar compounds without a phenyl substituent in the 4-position of the piperazinyl group and said to possess tranquilizing and psychopharmachodynamic properties, respectively.
AU Patent No 15658/83 discloses 3-(4-phenyl-1-piperazinyl-C2-4 alkyl)hydantoin compounds having antihypertensive effects.
WO 92/00282 relates to a subgroup of the compounds of U.S. Pat. No. 3,374,237 which are 1-phenyl-3-[4-(4-phenyl-1-piperazinyl)-1-butyl]-2-imidazolidinones having an optional chloro atom in the 2-position of the phenyl substituent in 1-position of the imidazolidinone ring and a methoxy or ethoxy substituent in the 2- and/or 3-position of the other phenyl substituent. The compounds show dopaminergic effects.
Clinical studies of known 5-HT1A partial agonists such as e.g. buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione, gepirone, 4,4-dimethyl-1-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-2,6-piperidinedione, and ipsapirone, 2-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3(2H)-one-1,1-dioxide, have shown that 5-HT1A partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that also full agonists are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharmacol., 1991, 6, S53).
There is also evidence, both clinical and preclinical, in support of the beneficial effect of 5-HT1A agonists in the treatment of depression, impulse control disorders and alcohol abuse (van Hest, Psychopharmacol., 1992, 107, 474; Schipper et al, Human Psychopharmacol., 1991, 6, S53; Cervo et al, Eur. J. Pharmacol., 1988, 158, 53; Glitz, D. A., Pohl, R., Drugs 1991, 41, 11; Grof et al., Int. Clin.Psychopharmacol. 1993, 8, 167-172; Ansseau et al., Human Psychopharmacol. 1993, 8, 279-283).
5-HT1A agonists and partial agonists inhibit isolation-induced aggression in male mice indicating that these compounds are useful in the treatment of aggression (Sanchez et al., Psychopharmacology, 1993, 110, 53-59).
Furthermore, 5-HT1A agonists have been reported to show antipsychotic effect in animal models (Wadenberg and Ahlenius, J. Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol.andToxicol., 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989, 32, 1052) and recent studies also indicate that 5-HT1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al. Pharmacol. Biochem. and Behav. 1994, 47, 509-513) suggesting that 5-HT1A agonists are useful in the treatment of the extrapyramidal side effects (EPS) induced by conventional antipsychotic agents such as haloperidol.
Damping of dopamine (DA) overactivity by the use of DA receptor blocking drugs is today the most important principle in the treatment of schizophrenia, in particular the positive symptoms thereof, and other psychoses. xe2x80x9cClassical neurolepticsxe2x80x9d such as haloperidol, cis(Z)-flupentixol and chlorpromazine are believed to induce antipsychotic effect via DA receptor blockade. Unfortunately, these classical neuroleptics also induce EPS, which seem to be correlated to the propensity of these compounds to induce catalepsy in rodents (Arnt et al. Neuropharmacology, 1981, 20, 1331-1334). A combination of 5-HT1A receptor agonism which may prevent EPS in man (cf. above) and dopamine receptor blockade to treat the positive symptoms of schizophrenia would thus be very advantageous.
Furthermore, 5-HT1A agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn, Eur. J. Pharm. 1991, 203, 213).
Pharmacological studies have been presented which indicate that 5-HT1A antagonists are useful in the treatment of senile dementia (Bowen et al, Trends Neur. Sci. 1992, 15, 84).
Both in animal models and in clinical trials, it has been shown that 5-HT1A agonists exert antihypertensive effects via a central mechanism (Saxena and Villalxc3x3n, Trends Pharm. Sci. 1990, 11, 95; Gillis et al, J. Pharm. Exp. Ther. 1989, 248, 851. 5-HT1A ligands may, therefore, be beneficial in the treatment of cardiovascular disorders.
Accordingly, agents acting both on the 5-HT1A receptor, including agonists, partial agonists and antagonists, and at the same time blocking the dopamine D2 receptor are believed to be of potential use in the therapy of such conditions, in particular in the treatment of psychosis, and thus being highly desired.
It has now been found that a novel series of phenylpiperazines, 4-phenylpiperidines and 4-phenyl-1,2,3,6-tetrahydropyridines posseses both central serotonergic 5-HT1A and antidopaminergic D2 activity.
Accordingly, the present invention relates to novel 4-phenylpiperazine, 4-phenylpiperidine and 4-phenyl-1,2,3,6-tetrahydropyridine compounds of general Formula I: 
wherein A is a spacer group selected from branched or straight chain C3-8 alkylene, C3-8 alkenylene and C3-8 alkynylene, and C3-7 cycloalkylene, said spacer group being optionally substituted with lower alkyl, aryl or hydroxy;
R1 is a branched C3-10 alkyl, C3-10 alkenyl or C3-10 alkynyl group, cycloalk(en)yl, cycloalk(en)yl-lower alk(en/yn)yl, trifluoromethylsulfonyl, or lower alkylsulfonyl,
R2-R5 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, lower alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy, cycloalkyl, cycloalkyl-lower alkyl, nitro, lower alkylamino, di-lower-alkylamino and trifluoromethylthio;
R9 and R10 are independently hydrogen, lower alkyl or they may be linked together, thereby forming an ethylene or propylene bridge;
W is O or S;
V is O, S, CR6R7, or NR8 wherein R6, R7, and R8 are independently chosen among hydrogen or lower alkyl or lower alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, aryl-lower-alkyl or aryl, or R6 and R7 are linked together to constitute a 3-7 membered spirojoined ring;
Z is xe2x80x94(CH2)mxe2x80x94, m being 2 or 3 or Z is xe2x80x94CHxe2x95x90CHxe2x80x94;
the dotted line, emanating from X, indicates an optional bond and when it does not indicate a bond X is N or CH and when it indicates a bond X is C;
any alkyl, cycloalkyl or cycloalkylalkyl group present being optionally substituted with one or two hydroxy groups, which again are optionally esterified with an aliphatic or aromatic carboxylic acid; and any aryl substituent present being optionally substituted with halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, acyl, trifluoromethyl, trifluoromethylsulfonyloxy, cycloalkyl, cycloalkylalkyl or nitro;
and pharmaceutically acceptable acid addition salts thereof.
The compounds of the invention have affinity for the 5-HT1A receptor and the dopamin D2 receptor in vitro and they show 5-HT1A agonistic or antagonistic as well as dopaminergic activity in vivo. Furthermore, the compounds lack cataleptogenic effect or are only weakly cataleptogenic in rats indicating a very low potential for inducing EPS in man. Accordingly, the compounds of the invention are considered useful as drugs for the treatment of psychosis, positive symptoms of schizophrenia, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, impulse control disorders, alcohol abuse, aggression, EPS induced by conventional antipsychotic agents, ischaemic disease states, senile dementia and cardiovascular disorders.
In another aspect, the invention provides a pharmaceutical composition comprising at least one novel 4-phenylpiperazine, 4-phenylpiperidine or 4-phenyl-1,2,3,6-tetrahydropyridine according to the invention as defined above or a pharmaceutically acceptable acid addition salt or prodrug thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect, the present invention provides the use of a 4-phenylpiperazine, 4-phenylpiperidine or 4-phenyl-1,2,3,6-tetrahydropyridine compound according to the invention or an acid addition salt or prodrug thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders and diseases.
Some of the compounds of general Formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention.
Prodrugs of the compounds of general Formula I are also embraced by the invention.
The term cycloalkyl designates a carbocyclic ring having 3-8 carbon atoms, inclusive, or a bicyclic or tricyclic carbocycle, such as adamantyl, and cycloalkenyl designate corresponding groups containing an unsaturated bond.
The term lower alkyl refers to branched or unbranched alkyl groups having from one to six carbon atoms inclusive. Examples of such groups are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl. Accordingly, the terms lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylcarbonyl and lower alkylamino refer to such groups in which the alkyl moiety is a lower alkyl group as defined above, such as methoxy, ethoxy, 1-propoxy, methylthio, ethylthio, 1-propylthio, 2-propylthio, methylsulfonyl, ethylsulfonyl, etc. Similarly, lower alkenyl and alkynyl, respectively, designate such groups having from two to six carbon atoms, inclusive. Preferred lower alkyl, alkenyl and alkynyl groups are those having up to four carbon atoms.
The term aryl refers to a mono- or bicyclic carbocyclic or heterocyclic aromatic group, such as phenyl, indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl, naphthyl, and furanyl, in particular phenyl, pyrimidyl, indolyl, and thienyl.
Halogen means fluoro, chloro, bromo or iodo.
Acyl refers to an arylcarbonyl, C1-18 alkylcarbonyl, Nxe2x80x2xe2x80x94(C1-18)alkyl- or Nxe2x80x2,Nxe2x80x2-di(C1-18)-alkylcarbonyl group.
The expression alk(en/yn)yl means that the group may be an alkyl, alkenyl, or alkynyl group.
In Formula I, A is preferably a xe2x80x94(CH2)nxe2x80x94 group wherein n is an integer of 3-8, inclusive, more preferably 4-6, inclusive. Most preferably n is 4.
R1 is preferably branched C3-6 alkyl, cycloalkyl, cycloalkyl-lower alkyl or trifluoromethylsulfonyl, more preferably 2-propyl, 2-methyl-1-propyl, 2-butyl, 3-pentyl, 2,2-dimethyl-1-propyl, tert-butyl, cyclopropylmethyl, cyclopentyl, 2,4-dimethyl-3-pentyl or trifluoromethylsulfonyl, in particular 2-propyl, cyclopentyl, cyclopropylmethyl or trifluoromethylsulfonyl.
R2-R5 are preferably hydrogen, halogen or cyano and more preferably they are all hydrogen or one of the substituents is halogen and the others are hydrogen. R9 and R10 are preferably both hydrogen.
Z is preferably xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 and V preferably designates Nxe2x80x94R8, wherein R8 is lower alkyl, cycloalkyl, phenyl or phenyl substituted with halogen, most preferably cyclohexyl, adamantyl, isopropyl or 4-fluorophenyl. W is preferably oxygen.
Preferred compounds are:
3-Cyclohexyl-1-[4-[4-[2-(2-propyloxy)phenyl]-1-piperazinyl]butan-1-yl]-2-imidazolidinone.
3-(4-Fluorophenyl)-1-[4-[4-[2-(2-propyloxy)phenyl]-1-piperazinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-(2-cyclopentyloxyphenyl)-1-piperazinyl]butan-1-yl]-2-imidazolidinone.
1-[4-[4-(2-Cyclopentyloxyhenyl)-1-piperazinyl]butan-1-yl]-3-(4-fluorophenyl)-2-imidazolidinone.
1-[3-[4-[2-(2-Propyloxy)phenyl]-1-piperazinyl]-1-propyl]-3-phenyl-2-imidazolidinone.
3-(4-Fluorophenyl)-1-[4-[4-[2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[3-[4-[2-(2-propyloxy)phenyl]-1-piperidinyl]-1-propyl]-2-imidazolidinone.
3-(2-Propyl)-1-[4-[4-[2-(2-propyloxy)phenyl]-1-piperidinyl]-1-butyl]-2-imidazolidinone.
3-Cyclohexyl-1-[6-[4-[2-(2-propyloxy)phenyl]-1-piperidinyl]hexan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-(2-cyclopropylmethyloxyphenyl)-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[2-(2,2-dimethylpropyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-1,3-dihydroimidazol-2-one.
3-(1-Adamantyl)-1-[4-[4-[2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-1,3-dihydroimidazol-2-one.
3-(4-Fluorophenyl)-1-[4-[4-[2-(2-trifluoromethylsulfonyloxy)phenyl]-1-piperazinyl]-butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[2-(2-trifluoromethylsulfonyloxy)phenyl]-1-piperazinyl]butan-1-yl]-2-imidazolidinone.
3-(4-Fluorophenyl)-1-[4-[4-[2-(2-trifluoromethylsulfonyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[2-(2-propyloxy)phenyl]-1,2,3,6-tetrahydropyridin-1-yl]butan-1-yl]-2-imidazolidinone.
3-(4-Fluorophenyl)-1-[4-[4-[2-(2-propyloxy)phenyl]-1,2,3,6-tetrahydropyridin-1-yl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[2-(cyclopropylmethoxy)phenyl]-1,2,3,6-tetrahydropyridin-1-yl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[2-(2-propyloxy)phenyl]-1,2,3,6-tetrahydropyridin-1-yl]butan-1-yl]-2,3-dihydroimidazol-2-one.
3-(1-Adamantyl)-1-[4-[4-[2-(2-propyloxy)phenyl]-1,2,3,6-tetrahydropyridin-1-yl]butan-1-yl]-2,3-dihydroimidazol-2-one.
3-Cyclohexyl-1-[4-[4-[2-(1,1-dimethylethyl)oxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[2-cyclopropyloxyphenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclopentyl-1-[3-[4-[2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[5-fluoro-2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[4-chloro-2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[5-bromo-2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[5-cyano-2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Adamantyl-1-[4-[4-[2-(2-propyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
3-Cyclohexyl-1-[4-[4-[2-(2,4-dimethyl-3-pentyloxy)phenyl]-1-piperidinyl]butan-1-yl]-2-imidazolidinone.
The acid addition salts of the invention are pharmaceutically acceptable salts of the compounds of Formula I formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.
The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route, for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, exipients, or other additive usually used in the art may be used.
Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg.
The total daily dose is usually in the range of about 0.05-500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention.
The invention moreover relates to a method for the preparation of the novel 4-phenylpiperazines, 4-phenylpiperidines and 4-phenyl-1,2,3,6-tetrahydropyridines of Formula I, comprising:
a) reacting a compound of Formula II with a compound of Formula III: 
xe2x80x83wherein R1-R5, R9, R10, X, V, W, Z, n, and the dotted line are as previously defined and Y is a suitable leaving group such as halogen, mesylate, or tosylate; or
b) reducing the amide carbonyl of a compound of Formula IV: 
xe2x80x83wherein R1-R5, R9, R10, X, V, W, Z, n, and the dotted line are as previously defined; or
c) reacting a compound of Formula V: 
xe2x80x83wherein R2-R5, R9, R10, X, V, W, Z, A and the dotted line are as previously defined with a compound R1Y wherein R1 is as previously defined and Y is a suitable leaving group such as halogen, mesylate, or tosylate; or
d) reductive alkylation of the NH group of a compound of the Formula VI: 
xe2x80x83wherein R1-R5, R9, R10, X, V, W, Z, A and the dotted line are as previously defined, with and aldehyde Rxe2x80x2CHO, a ketone Rxe2x80x3Rxe2x80x2xe2x80x3CO or a carboxylic acid Rxe2x80x2 COOH in which formulas Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 are groups which together with the nitrogen atom form Nxe2x80x94CH2Rxe2x80x2 and Nxe2x80x94CHRxe2x80x3Rxe2x80x2xe2x80x3 groups, respectively, which are embraced by the previous definition of V; or
e) reducing the double bond of the 1,2,3,-6-tetrahydropyridine derivative of Formula VII: 
wherein R1-R5, R9, R10, X, V, W, Z and A are as previously defined;
whereupon the compound of Formula I is isolated as the free base or a pharmaceutically acceptable acid addition salt thereof.
The reaction of a compound of Formula II with a compound of Formula III according to Method a) is performed in a suitable organic solvent such as acetone, methyl isobutyl ketone, ethanol, 2-propanol, N-methyl-2-pyrrolidinone, preferably at an elevated temperature, eg. at the boiling point of the solvent, and generally in the presence of a base (such as potassium carbonate or triethylamine).
The reduction according to Method b) is conveniently performed by use of LiAlH4, AlH3 or diborane in an inert solvent such as tetrahydrofuran, dioxane, or diethyl ether at room temperature or at a slightly elevated temperature.
The reaction of a phenol compound of Formula V according to Method c) is generally performed by initially generating the phenolate ion by addition of a strong base (eg. potassium tert-butoxide) in an inert solvent such as diethyl ether, tetrahydrofuran, toluene, or dimethoxyethane preferably at room temperature or below. The phenolate ion is subsequently reacted with the compound of formula R1Y at an elevated temperature, eg. at the boiling point of the solvent. Trifluoromethylsulfonyloxy derivatives are conveniently obtained by triflation (see methods in WO 93/11761 Patent publication) of the properly substituted phenols of Formula V. Triflic acid anhydride, N-phenyltrifluoromethanesulfonimide, and triflic acid chloride are preferred as triflating agents.
The reductive alkylation of a compound of Formula VI according to Method d) is generally performed under acidic conditions, eg. in acetic acid, using NaBH4, NaCNBH3 or catalytic (Pt or Pd as catalysts) hydrogenation. Temperatures are generally at room temperature or below.
The reduction of a tetrahydropyridinyl double bond of a compound of Formula VII according to Method e) is generally performed by catalytic hydrogenation at low pressure ( less than 3 atm.) in a Parr apparatus, or by using a reducing agent such as diborane in an inert solvent such as tetrahydrofuran, dioxane, or diethyl ether.
The 1-Unsubstituted 4-arylpiperazines of Formula II (X=N) are either commercially available or may be synthesized from the corresponding anilines and Nxe2x80x2,Nxe2x80x2-bis(2-chloroethyl)amine by refluxing in highboiling solvents as eg. chlorobenzene typically for some days (2-3) according to methods described in Martin et al. J. Med. Chem. 1989, 32 1052-1056.
The 4-Phenylpiperidines of Formula II (X=CH) are either commercially available or prepared as described in eg. U.S. Pat. No. 2,891,066; McElvain et al. J.Amer.Chem. Soc. 1950, 72, 3134; Bally et al Chem.Ber. 1887, 20, 2590. The corresponding 4-phenyl-1,2,3,6-tetrahydropyridines of Formula II (X=C) are prepared from N-protected 4-piperidones by addition of properly substituted phenyl lithium or phenyl magnesium halides followed by acid catalyzed water elimination. The N-protecting group (carbamate, benzyl, sulfonyl, acetyl) is finally removed in a conventional manner.
The synthesis of more specific compounds of Formula II are given in detail in the Experimental Section.
1-(3-Chloropropyl)-, 1-(4-chlorobutyl)-, 1-(5-chloropentyl)-, and 1-(6-chlorohexyl)-2-imidazolidinones or the corresponding 3-substituted 2-imidazolidinones were prepared according to methods in Perregaard et al. J.Med.Chem. 1992, 35, 1092-1101 or references cited therein, or the detailed methods are described below.